title: Lethal respiratory failure and mild primary hypothyroidism in a term girl with a de novo heterozygous mutation in the TITF1/NKX2.1 gene.
abstract: BACKGROUND
  Thyroid transcription factor 1 (TITF1/NKX2.1) is expressed in the thyroid, lung, ventral forebrain, and pituitary. In the lung, TITF1/NKX2.1 activates the expression of genes critical for lung development and function. Titf/Nkx2.1(-/-) mice have pituitary and thyroid aplasia but also impairment of pulmonary branching. Humans with heterozygous TITF1/NKX2.1 mutations present with various combinations of primary hypothyroidism, respiratory distress, and neurological disorders.
  
  
  OBJECTIVE
  The objective of the study was to report clinical and molecular studies of the first patient with lethal neonatal respiratory distress from a novel heterozygous TITF1/NKX2.1 mutation.
  
  
  METHODS
  This girl, the first child of healthy nonconsanguineous French-Canadian parents, was born at 41 wk. Birth weight was 3,460 g and Apgar scores were normal. Soon after birth, she developed acute respiratory failure with pulmonary hypertension. At neonatal screening on the second day of life, TSH was 31 mU/liter (N <15) and total T(4) 245 nmol/liter (N = 120-350). Despite mechanical ventilation, thyroxine, surfactant, and pulmonary vasodilators, the patient died on the 40th day.
  
  
  RESULTS
  Histopathology revealed pulmonary tissue with low alveolar counts. The thyroid was normal. Sequencing of the patient's lymphocyte DNA revealed a novel heterozygous TITF1/NKX2.1 mutation (I207F). This mutation was not found in either parent. In vitro, the mutant TITF-1 had reduced DNA binding and transactivation capacity.
  
  
  CONCLUSIONS
  This is the first reported case of a heterozygous TITF1/NKX2.1 mutation leading to neonatal death from respiratory failure. The association of severe unexplained respiratory distress in a term neonate with mild primary hypothyroidism is the clue that led to the diagnosis.
authors.affiliation: IRIBHM and Genetics Service, Erasme Hospital, Free University of Brussels ULB, B-1070 Brussels, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Maquet
authors.forename: Sabine
authors.initials: S
authors.lastname: Costagliola
authors.forename: Jasmine
authors.initials: J
authors.lastname: Parma
authors.forename: Christiane
authors.initials: C
authors.lastname: Christophe-Hobertus
authors.forename: Luc L
authors.initials: LL
authors.lastname: Oligny
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.forename: Yves
authors.initials: Y
authors.lastname: Robitaille
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vuissoz
authors.forename: Antoine
authors.initials: A
authors.lastname: Payot
authors.forename: Sophie
authors.initials: S
authors.lastname: Laberge
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
authors.forename: Guy
authors.initials: G
authors.lastname: Van Vliet
authors.forename: Johnny
authors.initials: J
authors.lastname: Deladoëy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D004247:DNA